Development of a preparation containing a poor water solubility organic compound as an active ingredient is usually difficult. For example, a significant number of oral preparations of poor water solubility or insoluble organic compounds have poor absorbability from the digestion tract or the like, and fluctuations are large, so that it is difficult to obtain stable drug efficacies. Most of the candidate organic compounds for new drugs, from which very excellent efficacies could be expected if the compounds had been appropriately absorbed into the body, have problems such as the interruption of development or lengthening of the development period, due to their low bioavailability. On the other hand, even among the compounds for medical use that have already been approved as drugs, there are many poor water solubility organic compounds. For example, one-third or more of the drugs listed in the US Pharmacopoeia are poorly soluble or insoluble in water. Thus, it can also be expected to improve the existing preparations to preparations having more excellent medicinal efficacy, by improving the bioavailability of these poor water solubility organic compounds. Therefore, development of a method for improving the bioavailability of such a poor water solubility organic compound is strongly desired.
Heretofore, in regard to the preparations containing a poor water solubility organic compound as an active ingredient, a method of producing such a preparation by solubilizing the organic compound with an organic solvent or an aqueous solution containing a surface active agent, has been frequently employed. However, the organic solvents that are included in the package inserts of the existing many injectable preparations of poor water solubility organic compounds, are highly possible to bring about events that are not preferable from a medical point of view. Thus, preparations that do not contain these solvents have been demanded.
On the other hand, concomitantly with the recent development in nanotechnology, high expectations can be placed on the applied research on nanoparticles alone or assemblages thereof, and the development of the particle pulverization technology is popular in many industrial fields. In the field of medicine as well, a method of finely pulverizing a poor water solubility organic compound into nanoparticles is attracting attention as a method for improving the bioavailability of the organic compound. When particles are finely pulverized, the specific surface area of the particles is drastically increased, and in many cases, excellent characteristics that could not be predicted come to be discovered. It is conceived that a progress in the technology of pulverization now enables development of preparations for medical use having preferable characteristics that could not be seen hitherto.
Since it is expected to have improvements in the bioavailability of a poor water solubility organic compound for medical use or in the suitability to formulation by finely pulverizing the organic compound, some finely pulverized, poor water solubility organic compounds are known.
For example, there is known a preparation containing a steroid or a steroid derivative, of which the center of the particle size distribution is 0.005 μm to 5 μm, and the 90% median diameter of the particle size distribution is 10 μm (see, for example, Patent Document 1). However, the dispersed particles described in this document have a broad particle size distribution, and the stability of the suspension is decreased by the influence of coarse particles that are present, mixed in an amount of a few percents. Furthermore, although the preparation is subjected to a sterilization treatment using a 0.2-μm membrane filter for the purpose of carrying out the production of eye drops and injectable preparations efficiently, the permeability is markedly decreased due to the influence of these coarse particles, and there is a problem that the sterilization treatment using a 0.2-μm membrane filter is difficult.
Several methods have been disclosed as the method of pulverizing such a poor water solubility organic compound for medical use. For example, there is disclosed (1) a method of adding a non-crosslinked surface modifying agent to a organic compound having low solubility, and thereby making the particle size of the organic compound small by a mechanical means (see, for example, Patent Document 2). Through this method, pulverized particles of an organic compound onto which a sufficient amount of a surface modifying agent is adsorbed so as to maintain the state of the average particle size being less than about 400 mm, can be produced. However, the particles essentially necessitate the surface modifying agent, and the Examples describe only the technique of nanolization by a bead mill. Thus, in this case, there was a problem that contamination is prone to occur under the effect of the abrasion of the beads.
As for the method of using the supercritical technique, for example, there is disclosed (2) a method for producing a pulverous preparation of a biologically active compound having a size at the (sub)micron level, the method including (i) a process for dissolving the biologically active compound in a compressed gas, liquid or supercritical fluid containing a surface modifying agent under elevated pressure, or dissolving the biologically active compound in compressed dimethyl ether optionally containing a surface modifying agent; (iia) a process for rapidly expanding the compressed solution of the process (i), and thereby precipitating the dissolved compound; or (iib) a process of spraying the compressed solution of the process (i) into an antisolvent phase optionally containing a surface modifying agent under reduced pressure, under atmospheric pressure or under elevated pressure; and (3) a process for optionally converting the antisolvent phase of the process (iib) to a pulverous preparation using a conventional powder process technique (see, for example, Patent Document 3). Through the method, finely pulverized particles of the sub-micron level having an average particle diameter of 5 to 5,000 nm, and preferably 200 to 1,000 nm, can be produced.
As another method using the supercritical technique, there is disclosed (3) a method for preparing submicron particles of a water-insoluble compound, particularly a drug, while simultaneously stabilizing the fine particulate suspension with the molecules of a surface modifying agent, by dissolving a water-insoluble compound in a liquefied gas, and rapidly injecting to expand the compressed solution of the compound and the surface modifying agent into an aqueous medium, or optionally by homogenizing the aqueous suspension thus prepared with a high pressure homogenizer (see, for example, Patent Document 4). In these methods using the supercritical technique, the organic compound is dissolved in an appropriate solvent or liquefied gas under supercritical or near-critical conditions, and the mixed liquid is ejected while expanding from a nozzle into a reduced pressure part, a gas or a liquid, to evaporate the solvent. Therefore, control of the production of fine particles is very difficult, and the system needs to be under a high pressure environment in order to establish the supercritical or near-critical conditions, resulting in high production costs, which is not preferable.
Furthermore, as a method of using a hard medium such as beads formed of ceramics, glass or steel, for example, there is disclosed (4) a method of adjusting the average particle diameter of a solid agrochemical active ingredient to 1 to 15 μm, by mixing particulate materials of the solid agrochemical active ingredient which is ductile and malleable at normal temperature and exhibits solidifiability even under storage at a temperature below melting point, a basic white carbon and a porous material, and impact grinding the mixture with a pin mill a hammer mill or the like, or milling the mixture in a high speed air stream with an air mill or the like (see, for example, Patent Document 5). There is also disclosed (5), an organic compound for ultraviolet absorbent having an average particle size in the range of 0.01 to 2 μm, which have been pulverized using a milling apparatus such as a rotary ball mill, as a composition for protecting the skin from sunlight or ultraviolet radiation (see, for example, Patent Document 6). In addition, (6) a method of micronizing a crude polycyclic organic pigment, by preliminarily milling a crude coarse organic pigment by dry milling, and wet-milling the resulting micronized pigment in an aqueous suspension in a stirred ball mill which is operated at a power density of more than 2.5 kW per liter of milling space and a peripheral stirrer speed of more than 12 m/s under the action of a grinding medium having a diameter of 1 mm or less (see, for example, Patent Document 7), and the like are disclosed. However, in these methods using hard media, the abrasion powder generated by the abrasion of the balls or the mill vessel at the time of stirring and milling, is incorporated into the pulverized organic compound particles, and therefore, there has been a problem of so-called contamination (see, for example, Non-Patent Document 1).
As a method of pulverizing a poorly soluble drug by impact grinding, there is disclosed (7) a method of producing ultrafine particles having an average particle size of 1 μm or less, by subjecting 2.5 parts by weight of a saccharide or a mixture with a sugar alcohol with respect to 1 part by weight of a poorly soluble drug, to grinding by high-speed stirring or impact grinding (see, for example, Patent Document 8). However, this method has a problem that it is difficult to prevent the generation of heat due to impact, in addition to the problem of the contamination by abrasion powder. Furthermore, due to the characteristics of the impact grinding apparatus, crystalline organic compounds are likely to become amorphous, and in the case where it is desired to maintain the crystal structure of the organic compounds, the method is unsuitable.
There are also disclosed methods of wet milling an organic compound without using a hard medium, so as to prevent the contamination by abrasion powder. For example, as a method for producing odorless silk fine particles, there is disclosed (8) a method of adding roast salt and diethylene glycol to a purified silk fiber powder, kneading the ingredients, and triturating the mixture into a powder having a size of 1 to 2 μm (see, for example, Patent Document 9). As a method for finely pulverizing a composition for food, for example, there is disclosed (9) a method of dispersing coarse particles in a dispersion medium, subsequently adding a powder of a food additive that is insoluble or poorly soluble in the dispersion medium, to the dispersion liquid, and pulverizing the mixture in a wet pulverizer (see, for example, Patent Document 10), or the like. In addition, as methods of pulverizing a pigment, (10) a method of wet grinding crude dioxazine together with an inorganic salt and an organic liquid such as an alcohol or a polyol (see, for example, Patent Document 11), (11) a method for conditioning a polycyclic pigment, by adding to a crude pigment, a solid grinding aid selected from the group consisting of sodium chloride, sodium sulfate and aluminum sulfate, and a glycol or a mixture of glycols, and treating the pigment in the presence of a metal halide (see, for example, Patent Document 12), and the like are disclosed.
However, the magnesium chloride included in the roast salt that is used in the method of (8), is decomposed during the heating process, and generates poorly soluble basic magnesium chloride. It is difficult to eliminate the basic magnesium chloride from finely pulverized organic compound particles, and the basic magnesium chloride causes contamination as does the abrasion powder. Furthermore, since the fine powder of food obtained by the method of (9) has an average particle diameter of about 5 μm, the method is not very satisfactory as a method for finely pulverizing an organic compound for medical use.
The methods of (10) and (11) describe that pigments having more excellent characteristics compared to conventional pigments can be produced, but it is unclear regarding the degree of fine pulverization, or whether the methods are fine pulverization methods that are applicable to organic compounds for medical use. Particularly, in regard to organic compounds that are active ingredients of pharmaceutical products, it is required that such a compound be finely pulverized while maintaining the crystal form. However, since dissolution of the organic compound in a medium liquid brings about dissolution and re-elution even with a trace amount, thus resulting in a crystal form that is different from the form prior to pulverization, or an amorphous form. Thus, it is known that selection of the medium liquid is very difficult (Pharmaceutical Development and Technology, Vol. 9, No. 1, pp. 1-13 (2004)). The organic pigment pulverized by the solvent-salt milling method described in (1) often develops a color due to the crystal structure, and the chemical structure has fewer substituents and high planarity of the molecule, thus giving a compact crystal structure. For this reason, there are many high melting point compounds (melting point being 350° C. or higher), and many of the compounds are characterized by having low solubility in solvents. The methods of (10) and (11) are conceived to be truly usable because the methods are used for pulverizing pigments, which have particularly low solubility even among poorly soluble organic compounds. Thus, in the case of applying these methods to an organic compound for medical use which, in many cases, has markedly different characteristics such as a sparse crystal lattice, low melting point or high solubility in solvents, as compared to pigments, it has been regarded such that the organic compound for medical use dissolves out in the solvent, and cannot be finely pulverized.
In addition, as a method which does not use a pulverization apparatus, for example, (12) a method of producing porous particles having an average particle diameter of 6 to 8 μm and have excellent aerodynamic properties by freeze-spray drying a protein, and using the particles in an inhalant, is disclosed (see, for example, Patent Document 13).
In the method of (12), since fine pulverization is carried out by freeze-spray drying a compound that has been dissolved in a solvent, if the solvent is not a solvent capable of subliming by freeze-drying, it is difficult to eliminate the solvent from the resulting finely pulverized organic compound particles. Therefore, for compounds other than physiologically acceptable ones, such as a protein, and can be dissolved in a solvent capable of freeze-drying, finely pulverized organic compound particles cannot be produced, even if the method is applied. Also, in the case of carrying out fine pulverization using this method, sufficiently small particles cannot be obtained, and fine particles having excellent suspension stability and permeability through 0.2-μm membrane, could not be produced.
Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No. 2006-89386
Patent Document 2: Japanese Patent No. 3602546
Patent Document 3: Japanese Patent Application National Publication No. 2002-511398
Patent Document 4: Japanese Patent Application National Publication No. 2002-518318
Patent Document 5: JP-A No. 2003-286105
Patent Document 6: JP-A No. 11-100317
Patent Document 7: U.S. Pat. No. 5,626,662
Patent Document 8: Japanese Patent No. 2642486
Patent Document 9: JP-A No. 2006-182992
Patent Document 10: JP-A No. 2004-330078
Patent Document 11: Japanese Patent No. 2683458
Patent Document 12: JP-A No. 58-17167
Patent Document 13: U.S. Pat. No. 6,284,282
Non-Patent Document 1: Kuwahara Yoshitaka, “Pulverization Process in Fine Pulverization Region and Contamination”, Cutting-Edge Pulverization Technologies and Applications, NGT (2005), p. 81-88.